4E-BP1 and 4E-BP2 double knockout mice are protected from aging-associated sarcopenia

Area of Science:

• Aging research
• Muscle physiology
• Metabolic pathways

Background:

• Sarcopenia, the age-related loss of muscle mass and function, is a growing concern.
• Mechanistic target of rapamycin (mTOR) pathway is linked to muscle development, but its downstream targets, like eukaryotic initiation factor 4E-binding proteins (4E-BPs), are poorly understood in skeletal muscle aging.
• 4E-BPs regulate mRNA translation initiation, impacting various physiological processes.

Purpose of the Study:

• To investigate the impact of 4E-BP1 and 4E-BP2 deletion on skeletal muscle mass, function, and homeostasis in aged mice.
• To characterize the metabolic alterations in skeletal muscle associated with 4E-BP loss using metabolomic and lipidomic profiling.

Main Methods:

• Utilized 24-month-old wild-type and 4E-BP1/4E-BP2 double knockout (DKO) mice.
• Assessed muscle mass and grip strength.
• Measured protein synthesis via ex vivo 14C-phenylalanine incorporation.
• Performed skeletal muscle metabolomic and lipidomic profiling.

Main Results:

• 4E-BP1/2 DKO mice showed increased muscle mass and grip strength.
• Protein synthesis was significantly higher in DKO mice under basal and stimulated conditions.
• Metabolomic analysis revealed altered amino acid homeostasis, carbohydrate metabolism (e.g., increased maltitol/lactitol), and reduced beta-oxidation indicated by acylcarnitine profiles.

Conclusions:

• Deletion of 4E-BPs improves skeletal muscle mass and function in aging mice.
• 4E-BP deletion leads to significant perturbations in skeletal muscle energy metabolism.
• 4E-BPs represent potential therapeutic targets for combating sarcopenia.